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PubMed1978

Tumors as clonal proliferation.

Cytogenetic studies indicate that most tumors are clonal (i.e. unicellular in origin) and have karyotypic alterations. These are not consistent, but non-random abnormalities are being increasingly identified by banding techniques, pointing to the sites on human chromosomes where genes important in neoplastic development are located. It is postulated that tumor progression occurs as a result of genetic lability within the neoplastic clone, leading to emergence of increasingly mutant subpopulations (often recognizable cytogenetically) with more malignant properties. In the context of this hypothesis, acute leukemia, chronic leukemia, and preleukemia can be viewed as differing only in the rate at which an abnormal hemic clone is expanding, with progression to a more aggressive phase (e.g. the "blast crisis" of chronic granulocytic leukemia) reflecting emergence of a new predominant subpopulation as the result of an additional genetic change. These concepts, and the cytogenetic data from which they have been derived, may help our understanding of basic tumor biology, and have some practical applications in the diagnosis of human neoplasms.

Cell Division↗
PubMed1985

Myeloproliferative disorders in patients with rheumatoid arthritis treated with total body irradiation.

Four patients with refractory rheumatoid arthritis were treated with total body irradiation administered in two sittings, 300 to 400 rads to each half of the body. All four patients had taken antimetabolites prior to receiving total body irradiation, and two continued to use them after total body irradiation. Two patients had taken alkylating agents before, and one had used them after total body irradiation. All patients showed clinical improvement. However, in two patients myeloproliferative disorders developed: a myelodysplastic preleukemia at 40 months after total body irradiation in one and acute myelogenous leukemia at 25 months in the other. Total body irradiation differs from total nodal irradiation in the total dose of irradiation (300 to 400 rads versus 2,000 to 3,000), and in the duration of the therapy (two sittings versus treatment over several weeks to months). Furthermore, the patients in the total body irradiation study frequently used cytotoxic drugs before and/or after irradiation, whereas in one total nodal irradiation study, azathioprine (2 mg/kg per day or less) was permitted, but no other cytotoxic agents were allowed. Rheumatologists may therefore face a binding decision when deciding to treat a patient with rheumatoid arthritis with either a cytotoxic drug or irradiation.

Aged↗
PubMed1986

Interstitial deletion of the long arm of chromosome 5 (5q-) in leukemia and other hematological disorders: clinical and biological relevance of variable breakpoint patterns.

From January 1983 to January 1985, we have found a deletion of the long arm of chromosome 5 (5q-) in the bone marrow cells of 8 patients; they represent consecutive patients referred to our institution for investigation and treatment of the following hematological disorders in whom the 5q- abnormality was found: acute nonlymphocytic leukemia (ANLL) (3), refractory anemia with excess blasts (RAEB) (2), preleukemia (PL) (1), sideroblastic anemia (SA) (1), refractory anemia (RA) (1). The deletion proved to be interstitial in all patients, with 3 different breakpoint patterns emerging: q13q33, q11.2q21, q11.2q33. Proximal breakpoint q11.2 was found only in patients with an initial diagnosis of ANLL. The common region deleted in all patients was comprised between bands q13q21. The clinical relevance and biological meaning of the heterogeneity of proximal and distal breakpoints found in this study are discussed.

Adult↗
PubMed1993

A role for mitochondrial DNA in the pathogenesis of radiation-induced myelodysplasia and secondary leukemia.

The onset of acute myeloid leukemia following ionizing radiation or alkylating agent exposure is antedated months to years by the development of 'preleukemia', or secondary myelodysplastic syndrome (sMDS). Mitochondrial abnormalities induced by chloramphenicol and clonal deletions of mitochondrial DNA (mt DNA) in the bone marrow create hematological defects similar to sMDS, and abnormal dimers of mt DNA are observed in acute leukemia. This suggests a role for mt DNA in the pathogenesis of sMDS and secondary leukemia. We outline disparate experimental evidence to support this concept and suggest a role for select protease inhibitors in the clinical management of this disorder.

Bone Marrow↗
PubMed1982

Abnormalities of chromosome No. 17 in myeloproliferative disorders.

In routine analyses, abnormalities of chromosome No. 17 were found in the bone marrow cells of 28 patients with Ph1-positive and three patients with Ph1-negative chronic myeloid leukemia (CML), 4 patients with acute nonlymphocytic leukemia (ANLL), and 4 patients with preleukemia. With three exceptions, all patients were in the blastic (CML) or the terminal phase. In 28 patients, the aberrant chromosome No. 17 arose by clonal evolution from the karyotype found at diagnosis or before the terminal phase. The abnormalities encountered were an isochromosome for the long arm, i(17q), (26 cases), translocations involving No. 17 (12 cases), trisomy 17 (three cases), and ring 17 (one case). In 35 patients, there was an unbalanced structural aberration of at least one of the No. 17 chromosomes. In every case (35/35), detailed analysis of the structurally abnormal No. 17 revealed loss of the distal part of the short arm (or possibly most of the short arm). Gain of the long arm (or at least its proximal part) was also common, but not invariably present (26/35). It is suggested that loss of 17p is a highly nonrandom event related to blastic crisis in CML and the terminal phase in other myeloid leukemias.

Acute Disease↗
PubMed1983

Cytogenetic study of 88 cases of refractory anemia.

Data obtained on 88 patients with refractory anemia or preleukemia, without previous cytotoxic treatment, showed medullar chromosomal abnormalities in 32%. In 45% of the cases, the disease had progressed to acute nonlymphocytic leukemia. A high frequency of acute transformation (78%) was observed in patients with abnormal clones. These results are different from those of the Second International Workshop on chromosomes in Leukemia. The discrepancies may be related to the difference between the cases selected for submission to the workshop and those of this study. Serial studies on 28 patients with abnormal karyotypes showed that two different populations of patients were investigated: one with a terminal smoldering phase of leukemia and the other with true preleukemic disease. In the latter group, no predictive karyotype evolution was seen.

Aged↗
PubMed1984

Hematologic manifestations associated with deletions of the long arm of chromosome 20.

We investigated 20 patients with hematologic disorders who had a clone of cells with a deletion of most of a chromosome #20 long arm (20q-) in the bone marrow. Three patients had polycythemia vera (PV), 6 had acute nonlymphocytic leukemia (ANLL), 8 had preleukemia (PL), and 3 had other myeloproliferative disorders. In our laboratory, a 20q- chromosome is found in 6% of patients with PV, 3% of patients with ANLL, and 1% of patients with PL. Among the 6 patients with ANLL and a 20q- abnormality, 3 had erythroleukemia. There were no apparent clinical differences among our patients with 20q- chromosomes compared with other patients with similar disorders who did not have a 20q- chromosome. The breakpoint of the 20q- anomaly, in each instance, was in band 20q11, but it occurred near the centromere at 20q1101 in 16 patients and at the distal part of this band at 20q1109 in 4 patients. Three of the 4 patients with a breakpoint at 20q1109 had PL.

Aged↗
PubMed1984

Groups of darkly stained chromosomes may be artifacts.

Groups or conglomerations of darkly stained chromosomes (GDSC) observed in this study appeared to be artifacts as they were strictly technique dependent. Two methods of cell fixation were compared. In method I, fixative was added drop by drop to cell pellets and agitated continuously over a rotamixer. In method II, a few drops of fixative were added to hypotonic solution suspended with cells and mixed using a Pasteur pipette. In 11 patients with acute myeloid leukemia (AML) and in one patient with preleukemia studied using method I, no GDSC were found in the total of 325 metaphases examined. In 36 patients with AML, one with Klinefelter's syndrome and one with neutropenia studied using method II, GDSC were found in 18 patients. A further comparative study using different methods for cell fixation was performed in three patients. The frequency of cells with GDSC varied sharply with different methods used in two patients. In one patient the cells with GDSC were analyzed in detail. The number of darkly stained chromosomes in each cell was found to vary from 4 to 14 with a mean of 8.26 and D- and G-group chromosomes were preferentially involved.

Adult↗
PubMed1986

Sideroblastic anemia associated with thrombocytosis and a chromosome 3 abnormality.

A unique patient with sideroblastic anemia and thrombocytosis with a recurrent and ultimately fatal thromboembolic phenomenon is described. Cytogenetic analysis of bone marrow metaphases revealed a pseudodiploid chromosome complement, 46,XY,ins(3;3)(q26;q21q26). The association of thrombocytosis and ins(3;3) in patients with preleukemia or myelogenous leukemia has been reported previously. The association of ins(3;3) and thrombocytosis in our patient with sideroblastic anemia suggests that the disorder may involve a hematopoietic progenitor cell capable of giving rise to all three cell lineages. Our findings also support the suggestion that a gene on the long arm of chromosome #3 may encode a protein that, at least in part, regulates megakaryopoiesis.

Adult↗
PubMed1987

Chromosomal subclonal evolution in paroxysmal nocturnal hemoglobinuria evolving into acute megakaryoblastic leukemia.

Four cytogenetic studies were performed in the course of a paroxysmal nocturnal hemoglobinuria evolving into acute megakaryoblastic leukemia. The clonal evolution was characterized by a unique structural change (9p) at the time of diagnosis, heralding an accelerated and complex karyotypic alteration including 5q-, 12p-, +21, -5, -7. At the terminal phase, the initial population was replaced within 1 week by a new overgrowing clone with -5, +8, +17. This suggests that the paroxysmal nocturnal hemoglobinuria-associated preleukemia and leukemic states share with acute nonlymphocytic leukemia the same nonrandom chromosomal changes.

Adult↗
PubMed1989

Densitometric measurements of C bands of chromosomes 1, 9, 16, and Y in leukemic and preleukemic disorders.

Fifty-six patients with blood disorders (23 with chronic myeloid leukemia, 14 with acute myeloblastic leukemia, seven with acute lymphoblastic leukemia, one with chronic lymphocytic leukemia, and 11 with preleukemia states) were studied. A quantitative and objective method of C band length analysis with well-matched controls was used. The C bands of chromosome pairs 1, 9, and 16 presented a normal distribution that was similar in patients and controls, whereas the Y chromosome presented an abnormal distribution. Smaller C bands in 1qh and higher indexes of intrapair heteromorphism in pairs 1 and 9 were detected in the CML group; the group of acute leukemias (myeloblastic and lymphoblastic) presented a smaller index only in pair 1qh. No other differences in length, heteromorphism, inversion frequency, or sex were detected.

Adult↗
PubMed1994

Rapid method for obtaining high-quality chromosome banding in the study of hematopoietic neoplasia.

The original impetus for this work was the need for a method to analyze chromosome abnormalities in patients with hematopoietic neoplasms immediately after bone marrow (BM) aspiration. We present an easy and reproducible procedure for obtaining G-bands simultaneously with chromosome preparations (utilizing trypsin through hypotonic shock). It provides chromosomes of good quality with satisfactory banding range (450-500) within only 6 hours after BM aspiration. Using this technique, in our series of 560 patients with preleukemia and leukemia, we consistently provided the banding quality that allowed all chromosomes of the karyotype to be identified in 96% of myelodysplastic syndromes (MDS) 91% of acute lymphocytic leukemia (ALL), and 94% of acute myeloid leukemia (AML) cases, and we also identified cytogenetically abnormal clones in 70% of AML patients. With the same success this technique is also applicable to other types of human cells: lymphocytes from peripheral blood (PB) and established cell lines. Furthermore, this technique conserves chromatin structure and permits high hybridization efficiency rate on prebanded chromosomes and identification of chromosome markers within 36 hours after BM aspirations.

Azure Stains↗
PubMed1988

The preleukemic syndrome (hematopoietic dysplasia).

It has been recognized for many decades that epithelial dysplasia can represent an early histological sign of epithelial neoplasia. So it is with hematopoietic tissue wherein dysplasia of bone marrow cells can be an early sign of impending acute myeloid leukemia. Although this 'preleukemic syndrome' of hematopoietic dysplasia can often be identified well in advance of the classic histological signs of acute leukemia, a wide variety of basic studies on bone marrow cells, from patients and from experimental animals with induced preleukemia, clearly indicate that the preleukemic marrow cells are members of a fully established neoplastic clone. Consequently, it is likely that the preleukemic syndrome is merely acute leukemia diagnosed earlier than usual and which, in some patients, can be very slowly progressive, and in others may not progress at all. This article reviews the evidence in support of the notion that the preleukemic syndrome is an 'early leukemia', places the preleukemic syndrome in the context of a larger group of myelodysplastic disorders, reviews the laboratory studies of value for both diagnosis and for use in the assessment of prognosis, and summarizes the therapeutic options available for the management of patients with this disorder.

Humans↗
PubMedDate not supplied

Fever of unknown origin due to preleukemia/myelodysplastic syndrome: the diagnostic importance of monocytosis with elevated serum ferritin levels.

Fever of unknown origin (FUO) is a common clinical diagnostic dilemma. In the elderly, causes of FUO most commonly include malignancy or infection, and less commonly include collagen vascular diseases. Among the collagen vascular diseases causing FUO in the elderly, polymyalgia rheumatica/temporal arteritis, and adult Still's disease (adult juvenile rheumatoid arthritis) are difficult diagnoses to prove. Among the infectious causes of FUO in the elderly are subacute bacterial endocarditis, intra-abdominal abscesses, and extrapulmonary tuberculosis. In the elderly, neoplastic causes of FUO include lymphomas, hepatomas, renal cell carcinomas, and hepatic or central nervous system metastases. Acute leukemias, particularly during "blast" transformation, may present as acute fevers in the absence of infection, but are rare causes of FUO. Preleukemia/myelodysplastic syndromes are exceedingly rare causes of FUO. We present a case of an elderly man who presented with findings that initially suggested adult Still's disease. Prolonged and profound monocytosis provided the key clue to his subsequent diagnosis of preleukemia/myelodysplastic syndrome. In this patient, a positive Naprosyn test result also suggested a neoplastic cause for his FUO. After months of prolonged fevers, myelocytes/metamyelocytes were eventually demonstrated in his peripheral smear during hospital evaluation. These findings, in concert with the persistent monocytosis, highly elevated ferritin levels, polyclonal gammopathy on serum protein electrophoresis, and eventual presence of myelocytes/metamyelocytes on peripheral smear, prompted a bone marrow test that demonstrated blast cells confirming the diagnosis of preleukemia myelodysplastic syndrome as the cause of this patient's FUO.

Aged↗
PubMed1986

Acute myelomonocytic leukemia: an unusual variant with both granulocytic and monocytic esterases in the leukemic cells.

By using the combination of alpha-naphthyl butyrate esterase and chloroacetate esterase for cytochemical detection of monocytes and granulocytes, respectively, we examined and identified five adult patients with acute myeloid leukemia whose leukemic cells often (20 to 30%) had the characteristics of both monocytes and granulocytes. All five patients were men, 23 to 82 years of age. Two patients had manifestations of preleukemia. One of these two patients had received treatment for lymphoma for 12 months before acute myelomonocytic leukemia was diagnosed. One patient had gum hypertrophy, and two had leukemia cutis. At the time of initial examination, four patients had blood leukocyte counts higher than 80,000/mm3 and one had leukopenia. Four patients received chemotherapy; three responded temporarily but died within 1 year after the myelomonocytic leukemia had been diagnosed. The patient with leukopenia has remained in complete remission for 2 years. With more frequent use of double esterase stains for classification of acute myeloid leukemias, this variant of acute myelomonocytic leukemia should be detected more often and its clinical behavior should be better understood.

Adult↗
PubMed1988

Hemopoietic lineage switch: v-raf oncogene converts Emu-myc transgenic B cells into macrophages.

Hemopoietic lineage commitment can be breached by concomitant expression of the c-myc and v-raf oncogenes. Switching to the myeloid lineage occurred frequently when B lineage cells, from either lymphomas or preleukemia bone marrow cells of Emu-myc transgenic mice, were infected with a retrovirus bearing v-raf. Cloned pre-B and B cell lines changed into either mature or immature macrophages as assessed by morphology, adherence, phagocytic activity, surface markers, and lysozyme production, but retained clonotypic immunoglobulin gene rearrangements. Although expression of the Emu-myc transgene was reduced or abolished in the more differentiated lines, the lines remained tumorigenic. The converted lines produced the myeloid growth factor GM-CSF, and most had karyotypic alterations. These results suggest that constitutive myc plus raf expression can provoke genetic reprogramming in lymphocytes.

Animals↗
PubMed1992

Treatment of premalignancy: prevention of lymphoma in radiation leukemia virus-inoculated mice by cyclosporin A and immunotoxin.

Radiation leukemia virus (RadLV)-induced preleukemic (PL) latency is characterized by the appearance of virus-infected PL cells in the thymus. The survival of these PL cells is dependent upon autostimulation with interleukin 4 (IL-4). We have intervened prophylactically in RadLV-induced preleukemia by using cyclosporin-A (CSA), which inhibits IL-4 production, and an immunotoxin (ITx) that kills PL cells. CSA efficiently inhibited IL-4 secretion from RadLV-induced PL and leukemic cells, and its administration to PL mice caused a significant delay in their death. An ITx consisting of anti-RadLV glycoprotein-70 (gp70) antibody coupled to ricin A chain efficiently inhibited protein synthesis in virus-infected cells in vitro and, when injected into PL mice, also delayed their death. Combined treatment with CSA and ITx prevented 75% of the treated PL mice from developing lymphoma. These results show that the development of malignancy from a premalignant state can be averted by a combination of therapeutic modalities that decrease the size and growth rate of the premalignant cell population.

Animals↗
PubMed1997

Mutant N-RAS induces erythroid lineage dysplasia in human CD34+ cells.

RAS mutations arise at high frequency (20-40%) in both acute myeloid leukemia and myelodysplastic syndrome (which is considered to be a manifestation of preleukemic disease). In each case, mutations arise predominantly at the N-RAS locus. These observations suggest a fundamental role for this oncogene in leukemogenesis. However, despite its obvious significance, little is known of how this key oncogene may subvert the process of hematopoiesis in human cells. Using CD34+ progenitor cells, we have modeled the preleukemic state by infecting these cells with amphotropic retrovirus expressing mutant N-RAS together with the selectable marker gene lacZ. Expression of the lacZ gene product, beta-galactosidase, allows direct identification and study of N-RAS-expressing cells by incubating infected cultures with a fluorogenic substrate for beta-galactosidase, which gives rise to a fluorescent signal within the infected cells. By using multiparameter flow cytometry, we have studied the ability of CD34+ cells expressing mutant N-RAS to undergo erythroid differentiation induced by erythropoietin. By this means, we have found that erythroid progenitor cells expressing mutant N-RAS exhibit a proliferative defect resulting in an increased cell doubling time and a decrease in the proportion of cells in S + G2M phase of the cell cycle. This is linked to a slowing in the rate of differentiation as determined by comparative cell-surface marker analysis and ultimate failure of the differentiation program at the late-erythroblast stage of development. The dyserythropoiesis was also linked to an increased tendency of the RAS-expressing cells to undergo programmed cell death during their differentiation program. This erythroid lineage dysplasia recapitulates one of the most common features of myelodysplastic syndrome, and for the first time provides a causative link between mutational activation of N-RAS and the pathogenesis of preleukemia.

Acute Disease↗